Tramadol, with the chemical name of 2-((dimethylamino)methyl)-1-(m-methoxyphenyl)-cyclohexanol (CAS RN: 27203-92-5), is an opioid analgesic agent used in the symptomatic treatment of moderate to severe neuropathic pains. The usual dose of tramadol (normally vehicled in the form of a hydrochloride salt) consists of two daily 50 mg doses, but may attain 400 mg daily. Tramadol is first eliminated hepatically. After oral administration, tramadol is extensively metabolised in the liver. Approximately 30% of the dose administered orally is excreted in the urine not having been metabolised while 60% of the dose is excreted in the form of metabolites.
Ketoprofen, with the chemical name of 2-(3-benzoylphenyl) propionic acid (CAS RN: 22071-15-4) is a non-steroid anti-inflammatory agent (NSAI) having remarkable analgesic, anti-inflammatory, antipyretic and anti-rheumatic properties. The usual posology for ketoprofen, which is normally vehicled in acid form, is of two daily 100 mg doses or three daily 50 mg doses. The exact metabolism of ketoprofen is unknown but, however, it has been ascertained that it is also extensively metabolised in the liver.
Despite interacting with a large number of drugs, tramadol is successfully used in certain combinations, with the notable existence of a commercial product containing a combination of tramadol and paracetamol (Ultracet®, Janssen Cilag).
Data from experiments relating to potential synergic effect of tramadol with specific NSAIs where provided in U.S. Pat. No. 5,516,803 (tramadol in combination with ibuprofen) and in a communication dated Aug. 12, 2000, referring to the publication of EP546676 A1 tramadol in combination with NSAIs, especially ibuprofen). Furthermore, the combined use of tramadol and ketoprofen, in injectable form, was described by Siyam et al. (Co-Administration of Tramadol and Ketoprofen Produces Marked Antinociceptive Synergy with Reduced Side-Effects, Anesthesiology 2003; 99: A996) and by Tuncer et al. (Adding ketoprofen to intravenous patient-controlled analgesia with tramadol after major gynecological cancer surgery: a double-blinded, randomized, placebo-controlled clinical trial, Eur J Gynaecol Oncol. 2003; 24(2):181-4), although it should be stressed that these publications do not contain experimental data that ascertain the existence of synergism with tramadol and ketoprofen when these drugs are administered orally.
With the intent of obtaining a product with an optimal efficiency and safety profile as well as greater ease of administration, the inventors herein ascertained that a combination of tramadol with ketoprofen administered orally could be especially interesting due to the high analgesic potential of tramadol associated with the anti-inflammatory and analgesic properties of ketoprofen.
However, it proved that physical-chemical interaction occurred in formulations where the active principles came into contact which resulted in the formation of a thick viscous mass hard to dissolve that could result in an alteration of the bioavailability of the drugs.
With the objective of resolving the problem of interaction and maintaining the bioavailability of the drugs unaltered when these are vehicled in solid pharmaceutical forms, the inventors herein ascertained that is was especially interesting to vehicle tramadol and ketoprofen in pharmaceutical forms and/or products that prevent contact between them and/or impede interaction between the two active principles.
To the best knowledge of the inventors herein, there does not exist in the current state-of-the-art any publication concerning the efficiency and safety of an oral administration of a pharmaceutical composition comprising a specific combination of tramadol and ketoprofen, or the physical-chemical interaction between such active principles when vehicled in pharmaceutical forms and/or products that provide contact between them.